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Neurodevelopmental disruption of cortico-striatal function caused by degeneration of habenula neurons.

ABSTRACT: The habenula plays an important role on cognitive and affective functions by regulating monoamines transmission such as the dopamine and serotonin, such that its dysfunction is thought to underlie a number of psychiatric conditions. Given that the monoamine systems are highly vulnerable to neurodevelopmental insults, damages in the habenula during early neurodevelopment may cause devastating effects on the wide-spread brain areas targeted by monoamine innervations.Using a battery of behavioral, anatomical, and biochemical assays, we examined the impacts of neonatal damage in the habenula on neurodevelopmental sequelae of the prefrontal cortex (PFC) and nucleus accumbens (NAcc) and associated behavioral deficits in rodents. Neonatal lesion of the medial and lateral habenula by ibotenic acid produced an assortment of behavioral manifestations consisting of hyper-locomotion, impulsivity, and attention deficit, with hyper-locomotion and impulsivity being observed only in the juvenile period, whereas attention deficit was sustained up until adulthood. Moreover, these behavioral alterations were also improved by amphetamine. Our study further revealed that impulsivity and attention deficit were associated with disruption of PFC volume and dopamine (DA) receptor expression, respectively. In contrast, hyper-locomotion was associated with decreased DA transporter expression in the NAcc. We also found that neonatal administration of nicotine into the habenula of neonatal brains produced selective lesion of the medial habenula. Behavioral deficits with neonatal nicotine administration were similar to those caused by ibotenic acid lesion of both medial and lateral habenula during the juvenile period, whereas they were different in adulthood.Because of similarity between behavioral and brain alterations caused by neonatal insults in the habenula and the symptoms and suggested neuropathology in attention deficit/hyperactivity disorder (ADHD), these results suggest that neurodevelopmental deficits in the habenula and the consequent cortico-striatal dysfunctions may be involved in the pathogenesis and pathophysiology of ADHD.

SUBMITTER: Lee YA

PROVIDER: S-EPMC3084869 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Neurodevelopmental disruption of cortico-striatal function caused by degeneration of habenula neurons.

Lee Young-A YA Goto Yukiori Y

PloS one 20110429 4

<h4>Background</h4>The habenula plays an important role on cognitive and affective functions by regulating monoamines transmission such as the dopamine and serotonin, such that its dysfunction is thought to underlie a number of psychiatric conditions. Given that the monoamine systems are highly vulnerable to neurodevelopmental insults, damages in the habenula during early neurodevelopment may cause devastating effects on the wide-spread brain areas targeted by monoamine innervations.<h4>Methodol ...[more]

PMID: 21559387

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Project description:Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a complex neuropsychiatric phenotype. In a recent meta-analysis we identified core regions of consistent neurodegeneration in premanifest HD in the striatum and middle occipital gyrus (MOG). For early manifest HD convergent evidence of atrophy was most prominent in the striatum, motor cortex (M1) and inferior frontal junction (IFJ). The aim of the present study was to functionally characterize this topography of brain atrophy and to investigate differential connectivity patterns formed by consistent cortico-striatal atrophy regions in HD. Using areas of striatal and cortical atrophy at different disease stages as seeds, we performed task-free resting-state and task-based meta-analytic connectivity modeling (MACM). MACM utilizes the large data source of the BrainMap database and identifies significant areas of above-chance co-activation with the seed-region via the activation-likelihood-estimation approach. In order to delineate functional networks formed by cortical as well as striatal atrophy regions we computed the conjunction between the co-activation profiles of striatal and cortical seeds in the premanifest and manifest stages of HD, respectively. Functional characterization of the seeds was obtained using the behavioral meta-data of BrainMap. Cortico-striatal atrophy seeds of the premanifest stage of HD showed common co-activation with a rather cognitive network including the striatum, anterior insula, lateral prefrontal, premotor, supplementary motor and parietal regions. A similar but more pronounced co-activation pattern, additionally including the medial prefrontal cortex and thalamic nuclei was found with striatal and IFJ seeds at the manifest HD stage. The striatum and M1 were functionally connected mainly to premotor and sensorimotor areas, posterior insula, putamen and thalamus. Behavioral characterization of the seeds confirmed that experiments activating the MOG or IFJ in conjunction with the striatum were associated with cognitive functions, while the network formed by M1 and the striatum was driven by motor-related tasks. Thus, based on morphological changes in HD, we identified functionally distinct cortico-striatal networks resembling a cognitive and motor loop, which may be prone to early disruptions in different stages of the disease and underlie HD-related cognitive and motor symptom profiles. Our findings provide an important link between morphometrically defined seed-regions and corresponding functional circuits highlighting the functional and ensuing clinical relevance of structural damage in HD.

Dataset Information

Neurodevelopmental disruption of cortico-striatal function caused by degeneration of habenula neurons.

Publications

Neurodevelopmental disruption of cortico-striatal function caused by degeneration of habenula neurons.

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